REVIEW ARTICLE

Accepted Date: 07-Feb-2011

Summary at a Glance ‐ 
 
The use of different antiglycaemic agents for diabetes mellitus in 
advancing kidney disease and in renal transplantation is reviewed.  
The benefits and possible side effects of conventional and new therapies 
including biguanides, sulphonylurea, thiazolidinediones, alpha‐glucosidase 
inhibitors, meglitinides, GLP‐1 agonists, DPP‐4 inhibitors and insulin are 
discussed. 

Title. Current and emerging antiglycaemic pharmacological therapies – the renal

perspective*

Running title. Renal perspective on antiglycaemic therapies

Author. Adnan Sharif

Institution. Renal Institute of Birmingham, Queen Elizabeth Hospital, Birmingham,

United Kingdom.

Contact Information.

Dr. Adnan Sharif, Renal Institute of Birmingham, Queen Elizabeth Hospital, Edgbaston,

Birmingham, B15 2TH, United Kingdom

(Tel) 0121 472 3334 (Fax) 012162705747 (Email) sharif_adnan@hotmail.com

Word count. 3464

This is an Accepted Article that has been peer-reviewed and approved

for publication in the Nephrology, but has yet to undergo copy-editing
and proof correction. Please cite this article as an “Accepted
Article”; doi: 10.1111/j.1440-1797.2011.01466.x

1
Abstract

Diabetes mellitus and chronic kidney disease are two major global epidemics, with a

significant overlap of patients with concomitant problems. Therapeutic guidelines for the

treatment of diabetes mellitus are continuously updated to reflect the growing

armamentarium of antiglycaemic agents at the disposal of clinicians. However, they

rarely focus on the significant caveats and limitations associated with pharmacological

delivery of glucose-lowering treatment in the context of advancing kidney disease or in

the presence of a renal allograft. Proposed consensus algorithms for the treatment of

hyperglycaemia may not be appropriate for individuals with co-existing renal disease and

it is imperative to ensure nephrologists maintain a thorough understanding of the

limitations of antiglycaemic treatments in the presence of renal insufficiency or a renal

allograft. The purpose of this review is to highlight the range of glucose-lowering

therapies at the disposal of the clinician, both currently available and in development, and

discuss the advantages and disadvantages of these pharmacological agents from a renal

perspective. A tailored and individualised approach to treatment of diabetes mellitus in

the context of renal disease is essential to maintain optimum care and this article should

act as a supplement to existing guidelines and treatment algorithms.

Keywords

Antiglycaemic agents, diabetes mellitus, kidney allograft, kidney disease

2
Diabetes mellitus and chronic kidney disease are global epidemics with a significant

population overlap. Diabetes mellitus is the commonest cause of end-stage renal failure

in the world, with 20 to 40% of diabetics developing diabetic nephropathy (1), and new

onset diabetes after kidney transplantation is reported in between 2 to 53% of recipients

dependent on the diagnostic criteria used (2). Therapeutic advances in the treatment of

hyperglycaemia have increased the armamentarium of antiglycaemic agents at the

clinician’s disposal, with many more drugs in varying stages of development. Guidelines

on the medical management of hyperglycaemia for individuals with type 2 diabetes

mellitus (3) or new onset diabetes after transplantation (4) are available. However, the

former ignores renal-specific issues due to its generic guidance of type 2 diabetics and the

latter transplantation guidelines from 2003 are now dated.

In the context of renal disease the efficacy, safety, and limitations of available

antiglycaemic agents must be acknowledged to ensure optimum treatment of

hyperglycaemia in patients with renal insufficiency or a renal allograft. The aim of this

article is to summarise our armamentarium of antiglycaemic agents from a renal

viewpoint, focusing on both currently available and developmental pharmacological

therapies, to aid in the management of these two major health burdens when they occur in

individuals concomitantly.

3
Currently available therapies (Table 1)

Biguanides

The biguanides, of which metformin is the only hypoglycaemic drug available, achieve

improvements in insulin sensitivity by actions on hepatic and muscle adenosine

monophosphate-activated protein kinase (AMPK) (5). Metformin is associated with

reductions in glycated haemoglobin (HbA1c) of between 1-2% and is the treatment of

choice for overweight people with type 2 diabetes mellitus, where is it either weight

neutral or can cause modest weight loss. Long-term data from the UKPDS trial

demonstrates a continued benefit for metformin with regards to both diabetes and

cardiovascular-related endpoints (6). Additional advantages of metformin therapy include

a low risk of hypoglycaemia and a small beneficial effect on abnormal lipid profiles.

The most dangerous side effect is the occurrence of lactic acidosis, although this is

considered exceptionally rare and equivalent in occurrence to metformin-induced

hypoglycaemia (7). In a recent retrospective analysis, metformin associated lactic

acidosis was responsible for just under 1% of intensive care unit admissions in a single-

centre over a 5-year period, with a mortality rate of approximately 30% (8). The risk of

lactic acidosis is increased in the context of renal insufficiency, due to the combination of

drug accumulation and decreased renal clearance of lactate (9). It should be noted that if

prescribed under specific study conditions, the incidence of metformin-induced lactic

acidosis is no different from other oral hypoglycaemic agents (10). The degree of renal

impairment at which metformin should be suspended is controversial, with some

clinicians arguing for a tolerance of a certain degree of renal impairment (up to a

4
creatinine of 220 mmol/l or 2.5 mg/dl) due to the constellation of benefits and advantages

of metformin therapy (11). There is no consensus on what renal threshold is acceptable

for continued metformin use and this confusion is the likely explanation for varying

degrees of prescribing practices for metformin amongst clinicians in the context of

varying degrees of renal impairment (12). Recent studies have suggested that

continuation of metformin is safe down to a minimum estimated glomerular filtration rate

(eGFR) of 30 mL/min and argue for a more pragmatic approach to the use of metformin

in patients with renal impairment (13).

Other rare side effects include megaloblastic anaemia secondary to interference of

vitamin B12 absorption. In the context of kidney transplantation, there are no specific

contra-indications although there is a potential for exacerbation of gastrointestinal

complaints with concomitant use of mycophenolate mofetil and there is no recognised

threshold of graft function at which metformin should be suspended for the risk of lactic

acidosis. Weight gain post kidney transplantation is common and therefore metformin

would be advantageous as a glucose-lowering agent in such individuals. In addition there

is accumulating evidence in the type 2 diabetic population suggesting a putative link

between metformin use and a reduced incidence of certain cancers (14), which would be

advantageous post-transplantation where malignancy is common.

Sulphonylureas

Sulphonylureas effectively reduce fasting hyperglycaemia and HbA1c by approximately

1-2%, with similar efficacy to metformin (15), by enhancing pancreatic beta cell insulin

5
secretion although there is a significant secondary failure rate with sulphonylureas, with

over half of patients started requiring insulin therapy by 6 years post commencement in

one study (16). The effects of sulphonylureas on cardiovascular endpoints have been

conflicting in the past, although recent analyses suggest there are worse long-term

cardiovascular outcomes with sulphonylureas compared to metformin (17).

Sulphonylureas have evolved over recent decades and can be differentiated by their

different pharmacokinetics. Older preparations, such as second generation glibenclamide

or glyburide, have a greater propensity to induce hypoglycaemia compared to newer

second generation (glipizide, gliclazide and glimepiride) preparations. This is, in part,

due to the presence of active metabolites or metabolites with significant hypoglycaemic

potency in older sulphonylureas compared to more recent preparations. In addition, older

sulphonylureas such as glibenclamide have been shown to diminish the counter-

regulatory glucagon secretion in reaction to hypoglycemia compared to newer agents

such as glimepiride (18).

Weight gain and hypoglycaemia are common side effects. Sulphonylureas should be used

with caution in mild to moderate renal failure, and completely avoided in severe renal

impairment, due to the increased risk of hypoglycaemia (likewise in the context of severe

liver impairment), although different sulphonylureas have different pharmacokinetics as

discussed above. No transplantation-specific related interaction is documented, but in the

context of impaired graft function the use of sulphonylureas may be limited. In addition,

6
the weight gain associated with these agents may exacerbate the weight gain often

observed post-transplantation and worsen other metabolic risk profiles.

Thiazolidinediones

Currently available thiazolidinediones, rosiglitazone and pioglitazone, are selective

agonists of the peroxisomal proliferator activated receptor gamma (PPAR-γ). They act as

prandial glucose regulators and improve insulin sensitivity in adipose tissue, skeletal

muscle and the liver. They are efficacious and associated with a 0.5-1.4% reduction in

HbA1c (3), although the long-term glycaemic durability may be superior with these

agents (19). Pioglitazone has been shown to reduce the occurrence of some

cardiovascular outcomes in patients with an eGFR less than 60 mL/min but at the risk of

a greater decline in renal function (20). Rosiglitazone has been safely used post kidney

transplantation and demonstrated good short-term efficacy (21), one of only two

antiglycaemic medications with any evidence base post-transplantation (neither in the

context of a randomised controlled trial).

A previously released PPARγ agonist troglitazone was withdrawn due to several cases of

fatal hepatotoxicity, but no similar problems have been associated with either

rosiglitazone or pioglitazone. Fluid retention (causing weight gain and reduced

hematocrit), higher fracture rates of distal extremities in females and some

gastrointestinal side effects have all been observed with both agents. Caution is advised

with PPARγ agonist use in patients with an eGFR less than 30 mL/min, although

problems with fluid retention would be much more likely in the context of advancing

7
chronic kidney disease. Of greatest concern, recent meta-analyses have shown that

although pioglitazone is associated with a reduction in the incidence of death, myocardial

infarct and stroke (22), similar analysis of rosiglitazone suggests an increased risk of

myocardial infarcts and heart failure (23, 24). This is despite both agents also showing

mild benefits on other cardiovascular risk profiles such as hypertension and

hypercholesterolemia. It should be highlighted that both rosiglitazone and pioglitazone

are associated with fluid retention and congestive cardiac failure. Lago et al. (25)

demonstrated a class effect of thiazolidinediones on the occurrence of congestive cardiac

failure, but not on cardiovascular death, in a meta-analysis of 7 randomised, double-blind

trials. Longer follow up of such study patients is required to clarify the overall

cardiovascular risk for patients on thiazolidinediones.

The current advice regarding thiazolidinediones from regulatory authorities are

specifically for rosiglitazone. Since September 2010, the Food and Drug Administration

(FDA) in the US has restricted the use of rosiglitazone to patients with type 2 diabetes

who cannot control their diabetes with other medications (26) whereas the European

Medicines Agency (EMA) has recommended suspending the marketing authorisation of

all rosiglitazone-containing medications (27). Cardiovascular disease is the leading cause

of death in both dialysis and transplant patients and current evidence suggests caution

with the use of both agents but favours the utilisation of pioglitazone if a PPARγ agonist

was desired.

8
Alpha-glucosidase inhibitors

These agents, which include acarbose, miglitol and voglibose, are enzyme inhibitors that

act in the intestines to attenuate the absorption of carbohydrates. Acarbose has been

shown to reduce HbA1c by approximately 0.8% in type 2 diabetics (3), although the

increased delivery of carbohydrates into the colon means gastrointestinal side effects are

very common and include flatulence, bloating, abdominal pain and diarrhoea. This

severely limits the utility of these agents as between 24-45% of patients will discontinue

these agents (3, 28).

In the context of renal impairment, acarbose is not recommended for use in individuals

with an eGFR less than 25 ml/min, although it is often overlooked for any degree of renal

insufficiency. Its use in kidney transplant recipients is also likely to be prohibited as its

concomitant use with mycophenolate mofetil could trigger gastrointestinal upset.

Meglitinides

The meglitinides, repaglinide and netaglinide, are short-acting agents that close the ATP-

dependent potassium channel on cell membranes of the pancreatic beta cell in a similar

fashion to sulphonylureas, resulting in depolarisation of cells and subsequent calcium

influx inducing insulin secretion. By administration pre-meals, it reduces postprandial

glycaemia and is associated with HbA1c reductions of up to 2.1% (repaglinide >

netaglinide) (29).

9
Side effects of the meglitinides include hypoglycaemia and weight gain, with

gastrointestinal symptoms rare. One of the significant advantages of meglitinides is the

safe administration of these agents in the context of even severe renal impairment

(repaglinide > netaglinide), as these drugs undergo hepatic clearance. To this effect,

repaglinide is one of the only drugs shown to be safe (minimal interaction with

immunosuppression) and efficacious (HbA1c lowering) post-transplantation (30) and is

considered the first-line agent for use in the context of new onset diabetes after

transplantation (2).

GLP-1 agonists

The two main gut hormones (or incretins) are glucagon like peptide 1 (GLP-1) and

glucose-dependent insulinotropic peptide (GIP), secreted by K-cells in the upper small

intestines. Gut hormones have been shown to have an important role in whole-body

glucose homeostasis by suppressing meal-related glucagon secretion, delay gastric

emptying and induce satiety (31), with GLP-1 having greater potency than GIP (32). As

the GLP-1 effect is diminished in type 2 diabetics, administration of exogenous GLP-1

would appear an attractive therapeutic option, although GLP-1 administration is severely

limited by rapid degradation from the enzyme dipeptidyl-peptidase 4 (DPP-4).

Most GLP-1 agonist experience currently is with exenatide, although longer acting

formulations of GLP-1 agonists such as liraglutide have been recently approved.

Exenatide is an analogue of GLP-1 resistant to DPP-4 degradation, and is administered as

a twice-daily subcutaneous injection. Despite augmenting insulin secretion,

10
hypoglycaemia is rare unless administered with concomitant antiglycaemic therapy like

sulphonylureas. They predominantly lower postprandial hyperglycaemia and are

associated with an approximate 1% lowering of HbA1c in clinical trials as add-on

therapy and produces modest weight loss (33-36), making it an attractive

pharmacological choice in overweight diabetics.

Cases of acute pancreatitis have been noted, although a causative link cannot be

determined. Exenatide can cause acute kidney injury (37), and the US Food and Drug

Administration (FDA) has recommended revisions to the prescribing information for

exenatide based upon post-marketing reports. As GLP-1 is renally cleared, it is not

recommended for patients with an eGFR less than 30 mL/min and should be used with

caution with an eGFR between 30-50 mL/min. GLP-1 agonists commonly cause

gastrointestinal upset (nausea, vomiting, retching and diarrhoea) and concomitant

administration with mycophenolate mofetil may prove problematic. In addition, GLP-1

agonists delay gastric emptying and this raises concerns about drug absorption with

regards to immunosuppression. As a foreign protein exenatide provokes antibody

production in about half of patients, which are low-affinity/low-titre and not associated

with any difference in efficacy or immune-system associated adverse events. In the

context of kidney transplantation, it is speculative as to whether these antibodies may

have any long-term detrimental immunological impact on the allograft.

DPP-4 inhibitors

The rapid degradation of gut hormones by DPP-4 led to the development of a new class

of antiglycaemics that target the DPP-4 enzyme, such as sitagliptin and vildagliptin. They

11
pose no intrinsic risk of hypoglycaemia, as incretin levels diminish with

normoglycaemia, although concomitant therapy with sulphonylureas may introduce an

element of risk. They produce an approximate 0.74% reduction in HbA1c and are weight

neutral, based upon a recent meta-analysis of 13 studies (36).

Gastrointestinal side effects are less common with DPP-4 inhibitors. Side effects include

an increased risk of infection (nasopharyngitis, urinary tracts infections) and headaches

(36). Altered liver function tests have been reported in rare cases. DPP-4 inhibitors are

not recommended for patients with moderate to severe renal insufficiency (eGFR < 50

mL/min), which restricts their use in a nephrological setting. However, the

pharmacokinetics of DPP-4 inhibitors vary amongst the different agents. Bergman et al.

(38) recommend dose reduction for patients with renal impairment treated with

sitagliptin, whilst a 52 week randomised controlled, double-blind, parallel group study

demonstrated sitagliptin to be generally well tolerated and effective in patients with

moderate (estimated GFR 30-50 ml/min) and severe (under 30 mls/min) renal impairment

(39). With regards to other class agents, a recent review of DPP-4 inhibitor

pharmacokinetics recommended dose reduction of saxagliptin daily for patients with

moderate to severe renal impairment but highlighted limited clinical experience of renal

dosing with vildagliptin (40). With regards to other side effects, the increased risk of

infections associated with DPP-4 inhibitors may be exacerbated post-transplantation in

the context of immunosuppression. Furthermore, DPP-4 inhibitors undergo limited

oxidative metabolism by the cytochrome P450 isoenzyme CYP3A4 (41) and may interact

with calcineurin inhibitors post-transplantation.

12
Insulin

Insulin is the most effective glucose-lowering agent with no effective ceiling of use with

regards to dosage. Numerous classifications of insulin therapy are available depending on

whether they are rapid, short, intermediate or long acting in nature. No clinical evidence

is available to decide on optimum timing or initiation of any particular insulin regimen

and insulin commencement is often based on a clinical decision based on individual

patient requirements. A recent Cochrane review of long-acting (glargine, determir)

versus Neutral Protamine Hagedorn insulin compared the results of the two preparations

in patients with type 2 diabetes mellitus (42). The analysis demonstrated only a minor

benefit on hypoglycaemic rates using long-acting agents versus NPH insulin, with no

difference in outcomes such as morbidity, mortality or quality of life. Limitations of

published material include short-term follow up (maximum study length 52 weeks),

definition of hypoglycaemia and in the, context of this review, limitations on study

participants with moderate to severe renal insufficiency. We therefore await not only

long-term results but also specific sub-analysis in patients with renal disease.

Side effects of insulin include the need for subcutaneous administration, weight gain and

risk of hypoglycaemia. Insulin therapy will involve continuous self-monitoring of blood

glucose. Insulin requirements often decrease in patients with end-stage renal failure

(possibly due to altered renal gluconeogenesis or clearance of insulin) and dose

adjustments are often required to minimize the risk of hypoglycaemia, especially with

individuals on dialysis (43). There has been a lot of speculation regarding diabetes and

the increased risk of certain cancers amongst diabetics, with insulin use considered to be

13
the causative mechanism. This has been put down to the interplay between insulin-like

growth factor 1 and neogenesis (44). However, it is difficult to ascertain whether the risk

of cancer is increased from insulin use per se or perhaps hyperglycaemia secondary to

delayed insulin commencement, a so called ‘glucose supply’ hypothesis (45). The

increasing occurrence of malignancy, especially in the context of transplantation, makes

this an important issue to resolve.

Emerging pharmacological therapies (Table 2)

SGLT2 inhibitors

A new class of antiglycaemics currently in development are the sodium-dependent

glucose transporter (SGLT) 2 inhibitors, which have been recently reviewed in detail

elsewhere (46). Briefly, renal handling of glucose normally occurs in the proximal tube

and consists of two types of glucose transporters: SGLT and glucose transporters

(GLUT). SGLTs accumulate glucose against a concentration gradient concurrently with

sodium. SGLT2 constitutes the low-affinity/high-flux transporter and in the early

segments of the proximal tubule, where it is coupled with GLUT2, is responsible for 90%

of filtered glucose reabsorption. Selectivity for SGLT2 has no impact on intestinal

reabsorption, which is SGLT1 dependent.

Diabetic individuals demonstrate abnormal expression of these glucose transporters and

decades ago it was shown that patients with diabetes mellitus have an increased ability to

reabsorb glucose in the proximal tubule (47). The potential advantages of SGLT2

inhibition include natriuresis (due to reduced sodium reabsorption) and their actions,

14
independent of insulin, have a low risk of hypoglycaemia. By contrast, the associated

glycosuria may increase the risk genitourinary infections (bacterial and fungal) and also

possible exacerbate diabetic nephropathy by activating pro-fibrotic pathways in the

proximal tubular cells.

Clinical trials investigating the use of SGLT2 inhibitors, including agents such as

dapagliflozin, canagliflozin, sergliflozin (now discontinued) and remogliflozin, are in

varying degrees of development and trials and we await definitive results of both efficacy

and side effects (including safety in the context of renal insufficiency and drug

interactions).

Glucokinase activators

Glucokinase catalyzes the conversion of glucose to glucose-6-phosphate, the first step of

glucose metabolism, and is expressed in neuronal, pancreatic and hepatic cells with an

important role in maintaining whole-body glucose homeostasis by acting as ‘glucose-

sensors’ (48). The potential benefits of glucokinase activators include dual action on both

pancreatic/hepatic cells and weight neutrality (and likely reduction). There is no clear

evidence of glucokinase distribution in the kidney, which could have an impact on renal

glucose sensing. Numerous compounds are in varying stages of development and trials,

although some compounds have been withdrawn after both Phase I and II trials, and

definitive clinical evaluation is awaited.

15
Glucagon antagonists

Excessive glucagons levels have been shown to exacerbate the hyperglycaemia observed

in diabetic individuals and the important role of glucagon in diabetes, antagonistic to

insulin, was documented many decades ago (49). Many pharmaceutical companies are

now developing compounds to act as glucagon antagonists, with preliminary data

showing short-term efficacy and safety in humans (50).

Bile acid sequestrants

Cholestyramine, colestimide and colesevelam are bile acid sequestrants used in the

management of hypercholesterolemia but recently the antiglycaemic effects of these

agents has been under investigation with modest reductions of approximately 0.5% in

HbA1c reported with colesevelam in combination therapy with either metformin or a

sulphonylurea (51, 52).

As they are not absorbed, gastrointestinal side effects are common with these agents.

Although constipation is the most common, diarrhoea, nausea and vomiting are also

commonly reported and could be exacerbated post-transplantation with mycophenolate

mofetil. In addition, absorption of fat-soluble vitamins is disrupted and patients can

become vitamin A, D and K deficient and require supplementation. Cases of

hypoglycaemia have been reported in trials but in the context of combination therapy. It

is safe to use in the context of renal impairment and would appear attractive due to

beneficial effects on both hyperglycaemia and hypercholesterolaemia.

16
Amylin analogues

Pramlintide is a synthetic analogue of the pancreatic beta-cell hormone amylin and aids

glucose absorption by delaying gastric emptying, increasing satiety and inhibits glucagon

production (53). It reduces HbA1c by approximately 0.5-0.7% and produces modest

weight loss in clinical studies when added to basal insulin (54).

Its side effects include hypoglycaemia and gastrointestinal complaints, especially nausea,

although the effects are likely to abate over time. It is administered subcutaneously pre-

meal and dosage adjustments are not required for patients with moderate renal

impairment (eGFR 20-50 ml/min), although no guidance is available for patients with an

eGFR less than this or on renal replacement therapy (55). At the present moment in time,

this agent is only available in the United States as adjunct therapy for individuals on

insulin therapy.

Conclusion

Despite the wide variety of antiglycaemic agents available, it can be appreciated that

there are several caveats and limitations to the application of some these agents to

patients with concomitant renal disease. Both diabetes mellitus and renal disease are

epidemic and it is inevitable that there will be a growing population of individuals who

overlap both clinical entities. Optimal pharmacological therapy for such individuals

requires a critical appraisal of existing guidelines in the context of concurrent renal

disease to ensure both safe and efficacious treatment for diabetics within the spectrum of

renal disease.

17
Acknowledgements

The author has no relevant disclosures or conflict of interest to declare.

References

1. Standards of medical care in diabetes--2010. Diabetes Care;33 Suppl 1:S11-61.

2. Davidson JA, Wilkinson A. New-Onset Diabetes After Transplantation 2003

International Consensus Guidelines: an endocrinologist's view. Diabetes Care

2004;27(3):805-12.

3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al.

Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the

initiation and adjustment of therapy: a consensus statement of the American Diabetes

Association and the European Association for the Study of Diabetes. Diabetes Care

2009;32(1):193-203.

4. Davidson J, Wilkinson A, Dantal J, Dotta F, Haller H, Hernandez D, et al. New-

onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings

of an international expert panel meeting. Barcelona, Spain, 19 February 2003.

Transplantation 2003;75(10 Suppl):SS3-24.

5. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-

activated protein kinase in mechanism of metformin action. J Clin Invest

2001;108(8):1167-74.

6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of

intensive glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.

7. Chan NN, Brain HP, Feher MD. Metformin-associated lactic acidosis: a rare or

very rare clinical entity? Diabet Med 1999;16(4):273-81.

18
8. Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE, et al. Metformin-

associated lactic acidosis in an intensive care unit. Crit Care 2008;12(6):R149.

9. Runge S, Mayerle J, Warnke C, Robinson D, Roser M, Felix SB, et al.

Metformin-associated lactic acidosis in patients with renal impairment solely due to drug

accumulation? Diabetes Obes Metab 2008;10(1):91-3.

10. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic

acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev

2006(1):CD002967.

11. Rachmani R, Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M. Metformin in

patients with type 2 diabetes mellitus: reconsideration of traditional contraindications.

Eur J Intern Med 2002;13(7):428.

12. Calabrese AT, Coley KC, DaPos SV, Swanson D, Rao RH. Evaluation of

prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med

2002;162(4):434-7.

13. Shaw JS, Wilmot RL, Kilpatrick ES. Establishing pragmatic estimated GFR

thresholds to guide metformin prescribing. Diabet Med 2007;24(10):1160-3.

14. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin

and reduced risk of cancer in diabetic patients. Bmj 2005;330(7503):1304-5.

15. Groop LC. Sulfonylureas in NIDDM. Diabetes Care 1992;15(6):737-54.

16. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR. Sulfonylurea

inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in

the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25(2):330-6.

19
17. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and

adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with

sulfonylureas and metformin. Diabetologia 2006;49(5):930-6.

18. Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman's The

Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill, 2006.

19. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J

Med 2006;355(23):2427-43.

20. Schneider CA, Ferrannini E, Defronzo R, Schernthaner G, Yates J, Erdmann E.

Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease.

J Am Soc Nephrol 2008;19(1):182-7.

21. Villanueva G, Baldwin D. Rosiglitazone therapy of posttransplant diabetes

mellitus. Transplantation 2005;80(10):1402-5.

22. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of

cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of

randomized trials. Jama 2007;298(10):1180-8.

23. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction

and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71.

24. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with

rosiglitazone: a meta-analysis. Jama 2007;298(10):1189-95.

25. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular

death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-

analysis of randomised clinical trials. Lancet 2007;370(9593):1129-36.

20
26.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatie

ntsandProviders/ucm226976.htm.

27.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/201

0/09/news_detail_001119.jsp&murl=menus/news_and_events/news_and_events.jsp&mi

d=WC0b01ac058004d5c1&jsenabled=true.

28. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose

treatment and the risk of cardiovascular disease and hypertension in patients with

impaired glucose tolerance: the STOP-NIDDM trial. Jama 2003;290(4):486-94.

29. Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide

analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007(2):CD004654.

30. Turk T, Pietruck F, Dolff S, Kribben A, Janssen OE, Mann K, et al. Repaglinide

in the management of new-onset diabetes mellitus after renal transplantation. Am J

Transplant 2006;6(4):842-6.

31. Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest

2007;117(1):24-32.

32. Green BD, Gault VA, Flatt PR, Harriott P, Greer B, O'Harte FP. Comparative

effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic

actions following substitution of Ala8/Ala2 with 2-aminobutyric acid. Arch Biochem

Biophys 2004;428(2):136-43.

33. Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, et al. A comparison

of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who

21
were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study.

Diabetologia 2007;50(2):259-67.

34. Zinman B, Hoogwerf BJ, Duran Garcia S, Milton DR, Giaconia JM, Kim DD, et

al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2

diabetes: a randomized trial. Ann Intern Med 2007;146(7):477-85.

35. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of

exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-

treated patients with type 2 diabetes. Diabetes Care 2005;28(5):1092-100.

36. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2

diabetes: systematic review and meta-analysis. Jama 2007;298(2):194-206.

37. Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide-associated ischemic

renal failure. Diabetes Care 2009;32(2):e22-3.

38. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, et al. Effect of renal

insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.

Diabetes Care 2007;30(7):1862-4.

39. Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, et al.

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal

insufficiency. Diabetes Obes Metab 2008;10(7):545-55.

40. Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes

Metab 2010;12(8):648-58.

41. Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, et al. Metabolism

and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug

Metab Dispos 2007;35(4):533-8.

22
42. Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, et al. Long-

acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes

mellitus. Cochrane Database Syst Rev 2007(2):CD005613.

43. Jackson MA, Holland MR, Nicholas J, Lodwick R, Forster D, Macdonald IA.

Hemodialysis-induced hypoglycemia in diabetic patients. Clin Nephrol 2000;54(1):30-4.

44. LeRoith D, Roberts CT, Jr. The insulin-like growth factor system and cancer.

Cancer Lett 2003;195(2):127-37.

45. Johnson JA, Gale EAM. Diabetes, Insulin Use, and Cancer Risk: Are

Observational Studies Part of the Solution–or Part of the Problem? Diabetes

2010;59(5):1129-1131.

46. Mather A, Pollock C. Renal glucose transporters: novel targets for hyperglycemia

management. Nat Rev Nephrol 2010;6(5):307-11.

47. Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal

hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects.

Scand J Clin Lab Invest 1971;28(1):101-9.

48. Matschinsky FM. Assessing the potential of glucokinase activators in diabetes

therapy. Nat Rev Drug Discov 2009;8(5):399-416.

49. Unger RH, Orci L. Role of glucagon in diabetes. Arch Intern Med

1977;137(4):482-91.

50. Petersen KF, Sullivan JT. Effects of a novel glucagon receptor antagonist (Bay

27-9955) on glucagon-stimulated glucose production in humans. Diabetologia

2001;44(11):2018-24.

23
51. Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride

therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid

effects. Arch Intern Med 2008;168(18):1975-83.

52. Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl

improves glycemic control and reduces LDL cholesterol in patients with inadequately

controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care

2008;31(8):1479-84.

53. Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the

treatment of diabetes. Diabetes 2004;53 Suppl 3:S233-8.

54. Riddle M, Frias J, Zhang B, Maier H, Brown C, Lutz K, et al. Pramlintide

improved glycemic control and reduced weight in patients with type 2 diabetes using

basal insulin. Diabetes Care 2007;30(11):2794-9.

55. Ryan G, Briscoe TA, Jobe L. Review of pramlintide as adjunctive therapy in

treatment of type 1 and type 2 diabetes. Drug Des Devel Ther 2009;2:203-14.

24
 Table 1 – Currently available antiglycaemic agents

Adjustment in renal

Mechanism of failure (British National

Agent Advantages Disadvantages
action Formulary:

www.bnf.org)

Efficacy (micro and Gastrointestinal side eGFR 30-45mL/min

Biguanides macrovascular endpoints), effects, risk of lactic (caution)
Insulin sensitising
(metformin) no hypoglycaemia, no acidosis in renal
weight gain, drug cost impairment eGFR < 30mL/min (avoid)
Sulphonylureas Hypoglycaemia, weight
Stimulation of Efficacy (microvascular
(glipizide, gain, accumulates in renal ⇓ dose
insulin secretion endpoints), drug cost
gliclazide etc.) failure
Thiazolidinediones Weight gain, oedema, drug
More sustained glucose
(rosiglitzazone1, Insulin sensitising cost, adverse None specific
2
control 1
pioglitazone ) cardiovascular effects
Meglitinides Reduces postprandial Hypoglycaemia, weight
Stimulation of
(repaglinide1, hyperglycaemia, safe with gain, drug cost, dose None specific
3
insulin secretion 1 3
nateglinide ) advancing renal failure adjustment in renal failure
Decreases
Alpha glucosidase
gastrointestinal No hypoglycaemia, weight Gastrointestinal side
inhibitors eGFR < 25mL/min (avoid)
carbohydrate neutral effects
(acarbose)
absorption
Stimulates insulin Gastrointestinal side
secretion, No weight gain (possible effects, risk of pancreatitis eGFR 30-50mL/min (use
GLP-1 agonists
decreases reduction), low risk of altered drug absorption, with caution)
(exenatide1,
glucagon hypoglycemia, lowers blood drug cost, renal
liraglutide)
production, pressure impairment, antibody eGFR < 30mL/min (avoid)
1
stimulates satiety production
Dose adjustment in renal
DPP-4 inhibitors Decreases
failure, drug cost, risk of
(sitagliptin, inactivation of No weight gain eGFR < 50mL/min (avoid)
pancreatitis, possible CNI
vildagliptin) incretins (GLP-1)
interaction
Exogenous Efficacy (micro and Weight gain, subcutaneous
Insulin administration of macrovascular endpoints), administration, Often ⇓ requirement
primary no ceiling of treatment, hypoglycaemia, putative

25
 glycaemia range of insulin types for link to certain cancers
countering individualisation
hormone
GLP-1 – glucagon-like peptide 1, DPP-4 – dipeptidase-4, CNI – calcineurin inhibitor,

eGFR – estimated glomerular filtration rate

26
 Table 2 –Antiglycaemic agents in development

Agent Mechanism of action Advantages Disadvantages

Glycosuria may increase

Possible natriuretic
risk of genitourinary
Block renal glucose effect, action
infections and
SGLT2 inhibitors reabsorption in the independent of insulin,
exacerbate pro-fibrotic
proximal tubule little risk of
pathways, risk of
hypoglycemia
dehydration

Activate glucokinase Dual action on both Safety (glucokinase

‘glucose-sensors’ in both liver and pancreas, expressed in neuronal

Glucokinase inhibitors
pancreatic and hepatic weight neutral (possible cells), effect on kidney

cells reduction) unknown

Blocks the antagonistic Glucagon integral to

Awaiting further
Glucagon antagonists action of glucagon versus whole body glucose
investigation
insulin homeostasis

Bile acid sequestrants Beneficial effects on Gastrointestinal side

Unknown (possible
(cholestyramine, abnormal lipid profiles, effects very common,
pleiotropic effect of lipid
colestimide, safe in renal disruption of fat-soluble
lowering)
colesevelam) impairment vitamin absorption

Synthetic analogue of beta- Subcutaneous

Weight neutral
cell hormone amylin – administration, risk of
(possible reduction),
delays gastric emptying, hypoglycaemia,
Amylin analogues safe in mild to
increases satiety and gastrointestinal side
moderate renal
inhibits glucagon effects, not available
impairment
production outside United States

SGLT – sodium-dependent glucose transporters

27